Cancer is a disease of uncontrolled cell division. Tumor cells achieve this state by overriding signals from growth inhibitory factors such as Transforming Growth Factor-β (TGFβ) [2-4] and acquiring constitutive activation of mitogenic signaling pathways such as the mammalian Target of Rapamycin (mTOR)/p70s6k pathway [5,6]. It has been demonstrated that activation of the TGFβ signaling pathway and simultaneous inactivation of mTOR signaling by the TOR inhibitor rapamycin synergize to inhibit the proliferation of human mammary carcinoma cells [7,8]. TGFβ+rapamycin-induced inhibition of cancer cell proliferation is caused by a dramatic increase in the association of the cyclin-dependent kinase inhibitor p27kip1 with the cyclin-dependent kinase Cdk2.
Despite the potent cytostatic action of TGFβ+rapamycin treatment on cancer cells in vitro, it is unlikely that this therapeutic strategy can be directly employed clinically. In addition to inhibiting cell proliferation, TGFβ also exhibits pro-tumorigenic [9-11] and pro-fibrotic [12] effects, and it would be difficult to deliver to cancers. Rapamycin derivatives RAD001 and CCI-779 are currently in clinical trials against several types of human tumors, and based on current data, have the potential to prove useful as cancer therapeutics. A drawback of using rapamycin as a cancer therapeutic is that it acts as an immunosuppressant by inhibiting the proliferation of B-cells and T-cells in addition to inhibiting cancer cell division.